BSP-Diol restores PKM2 and facilitates β-catenin–dependent epithelial repair in experimental colitis

Background Impaired mucosal healing is a major determinant of persistent inflammation and relapse in inflammatory bowel disease (IBD). Although repair-associated signaling pathways such as β-catenin can remain active during inflammation, epithelial regeneration is frequently insufficient. The mechanisms limiting proliferation-dependent repair in the context of inflammatory colitis remain incompletely defined. Methods The therapeutic effects of the Huanglian–Baiji herb pair were evaluated in a dextran sulfate sodium (DSS)–induced colitis model. An integrated strategy combining component prioritization with experimental validation was applied to identify active constituents and regulatory nodes. The effects of BSP-Diol on epithelial repair were examined in vivo and in vitro, focusing on epithelial proliferation, goblet cell recovery, β-catenin nuclear localization, and PKM2 regulation. The requirement of PKM2 was assessed using protein profiling and loss-of-function approaches. Results Huanglian–Baiji treatment significantly promoted epithelial proliferation and goblet cell restoration in DSS colitis. BSP-Diol was identified as a key component that restored β-catenin nuclear localization in inflamed epithelium. Inflammatory conditions markedly reduced PKM2 protein abundance, coinciding with impaired proliferative responses. Restoration of PKM2 by BSP-Diol facilitated β-catenin–dependent epithelial proliferation. In contrast, transcriptional regulators of mitochondrial biogenesis exhibited only modest changes, indicating predominant regulation at the protein and subcellular levels. PKM2 knockdown significantly attenuated BSP-Diol–induced β-catenin nuclear localization, demonstrating that PKM2 is required for effective repair signaling. Conclusions These findings identify PKM2 as a critical metabolic regulator of β-catenin–dependent epithelial repair in experimental colitis. Restoration of PKM2 relieves inflammation-associated metabolic constraints and promotes mucosal regeneration. Targeting metabolic regulation may represent a complementary strategy to enhance epithelial repair in IBD.